The aim of the research program proposed here is to explore how established drugs influence solute and water transport across simple epithelia,: such as capillary endothelium, peritoneal mesothelium, amphibian bladder and lung, hamster yolk sac and renal tubules. The experiments are expected to clarify: (a) mechanisms of solute transfer across epithelial barriers, with special emphasis on diffusion; (b) the process of water transfer across epithelial barriers; (c) humoral and neural mechanisms that may control and regulate epithelial permeability in health and disease. In characterizing transport processes across epithelia, many different phenomena must be considered and, where appropriate, measured (e.g., the electrochemical gradient, unidirectional flux constants, tissue pool of transported solute, etc.). Furthermore it is essential to consider mechanisms that serve to minimize back-diffusion, notably the metabolic destruction of the solute, its sequestration by tissue binding sites or by specific drug receptors, and removal by diffusion and by bulk flow. Experiments in these areas are expected to generate information that will serve many practical purposes. For example, a useful method for detecting and evaluating local drug effects on the transport capacity of tissue capillaries has been developed. It will be exploited in laboratory animals to examine drugs used in the treatment of coronary ischemia (angina pectoris). Other studies are expected to clarify the renal toxicity of radiographic contrast agents and the modes of action of some teratogenic substances. Factors that influence acute desensitization of isolated tissues to directly acting agonists will also be examined.